Comparison of vonoprazan and proton pump inhibitors for the treatment of gastric endoscopic submucosal dissection-induced ulcer: an updated systematic review and meta-analysis

Background Both vonoprazan and proton pump inhibitors (PPIs) are currently used to treat artificial ulcers after gastric endoscopic submucosal dissection. However, evidence-based medicine proving the efficacy of vonoprazan is still lacking. Therefore, this meta-analysis aimed to compare the efficacy of vonoprazan and PPIs for the treatment of artificial ulcers after gastric endoscopic submucosal dissection. Methods The PubMed, EMBASE and Cochrane Library databases were searched up to September 2023 for related randomized controlled trials (RCTs). RCTs that compared the efficacy of vonoprazan and PPIs in treating artificial gastric ulcers after gastric endoscopic submucosal dissection were included. Two independent reviewers screened the included studies, extracted the data and assessed the risk of bias. The following outcomes were extracted for comparison: ulcer healing rate, ulcer shrinkage rate, delayed postoperative bleeding rate, and ulcer perforation rate. Results Nine randomized controlled trials involving 926 patients were included. The pooled results showed that vonoprazan had a significantly lower rate of delayed postoperative bleeding than did PPIs (RR = 0.46; 95% CI = 0.23–0.91; P = 0.03). No significant differences were found in terms of ulcer healing, shrinkage rates, or ulcer perforation rates between vonoprazan and PPIs. Conclusions Compared with PPIs, vonoprazan is superior at reducing delayed postoperative bleeding after endoscopic submucosal dissection. However, further studies are needed to prove the efficacy of vonoprazan. Systematic Review Registration Identifier CRD42024509227. Supplementary Information The online version contains supplementary material available at 10.1186/s12876-024-03198-8.

Comparison of vonoprazan and proton pump inhibitors for the treatment of gastric endoscopic submucosal dissection-induced ulcer: an updated systematic review and meta-analysis Background Endoscopic submucosal dissection (ESD) has become the established treatment for early gastric cancer [1][2][3].Unfortunately, ESD can cause artificial ulceration, which is occasionally linked to delayed postoperative bleeding and even perforation [4,5].Proton pump inhibitors (PPIs) are generally prescribed after ESD to inhibit the secretion of gastric acid and to promote the healing of iatrogenic ulcers [6][7][8].
Recently, vonoprazan, a novel acid inhibitor, has been used after ESD.As an active potassium-competitive acid blocker (P-CAB), vonoprazan inhibits gastric acid secretion in a K+-competitive and reversible manner [9][10][11] and reportedly has a more rapid, stronger and longerlasting acid inhibitory effect than PPIs [11,12].Furthermore, vonoprazan is not affected by mealtimes or by CYP2C19 polymorphism [13,14].These findings indicate that vonoprazan may have a similar or better effect than PPIs have on the healing of ESD-induced ulcers.
Several studies [15][16][17] and meta-analyses [18,19] have been performed to compare the efficacy of vonoprazan and PPIs for treating post-ESD artificial ulcers.However, evidence-based medicine proving the efficacy of vonoprazan and PPIs is still lacking.Whether vonoprazan is superior to PPIs remains controversial.For example, the meta-analysis by Kang et al. [18] showed no substantial difference in ulcer healing between vonoprazan and PPIs, while the meta-analysis by Liu et al. [19] noted that vonoprazan had better efficacy in ulcer healing than did PPIs.Therefore, we conducted an updated systematic review and meta-analysis to compare the efficacy of vonoprazan and PPIs in treating ESD-induced artificial ulcers.

Methods
This meta-analysis was performed in accordance with a registered protocol (CRD42024509227).

Inclusion criteria
Studies were included if they met the following inclusion criteria: (1) target population: patients who underwent ESD, (2) intervention: vonoprazan versus PPIs, and (3) methodological criteria: randomized controlled trials (RCTs).Case reports, case series, and review articles were excluded.

Quality assessment
The quality of the included RCTs was independently assessed by two authors (J, D. and H. D.).Disagreements were resolved after discussion with another author (C.X.).For the included RCTs, we used the 12 criteria and instructions recommended by the Cochrane Back Review Group [18] for quality assessment.

Data extraction
Two authors (C.L. and J.D.) extracted the data from the included studies independently.The general characteristics of each study were collected, namely, year of publication, author, study design, sample size, duration of follow-up, and patient characteristics.The following outcomes were extracted for comparison: ulcer healing post-ESD at 4 and 8 weeks, shrinkage rate at 4 and 8 weeks post-ESD, delayed postoperative bleeding, ulcer perforation, and adverse events (AEs).The follow-up time for AEs was 4 or 8 weeks post-ESD.

Data analysis
Data analysis and synthesis were performed using Review Manager version 5.3 (Cochrane Collaboration).Continuous outcomes are expressed herein as the mean difference (MD) and 95% confidence interval (CI), and dichotomous outcomes are expressed as the risk ratio (RR) and 95% CI.The statistical heterogeneity among the included studies was evaluated using the χ2 test.P < 0.10 or I 2 > 50% indicated substantial heterogeneity.Heterogeneous data were evaluated by a random-effects model [20]; otherwise, a fixed-effects model was used [21].P < 0.05 was considered to indicate a statistically significant difference.

Literature search
A total of 176 articles that could potentially be included in this meta-analysis were identified.Of these articles, 150 were excluded after briefly screening the title, abstract, or full text.Ultimately, nine RCTs [15][16][17][22][23][24][25][26][27] were included for analysis in this study.The retrieval flow diagram is displayed in Fig. 1.

Study characteristics
Nine RCTs comparing the efficacy of vonoprazan and PPIs for managing ulcers post-ESD were included in the meta-analysis.The sample sizes of the nine RCTs ranged from 26 to 196.Overall, 470 patients in the vonoprazan group and 456 in the PPI group were included in this meta-analysis.Patients in the vonoprazan group received 20 mg vonoprazan or 20 mg vonoprazan plus 300 mg rebamipide daily.Patients in PPIs group were given 30 mg lansoprazole, 20 mg esomeprazole, 10 mg rabeprazole, or 20 mg esomeprazole plus 300 mg rebamipide daily.In the perioperative period, all patients received intravenous PPIs for one [27] or two [15][16][17]23] days in five studies [15-17, 23, 27].Then oral vonoprazan or oral PPIs were taken for 4 or 8 weeks.In the other four studies [22,[24][25][26], only oral vonoprazan or oral PPIs were taken by patients in the perioperative and follow-up periods.The main characteristics of the included studies are summarized in Table 1.

Quality assessment
All the included nine studies had a randomized design.The quality of the included RCTs was assessed by the Cochrane assessment tool.The assessment of various items showed a medium risk of bias among the included studies (Fig. 2).

Shrinkage rate Shrinkage rate at 4 weeks post-ESD
Two studies [22,26] including 278 patients reported differences in the shrinkage rate at 4 weeks post-ESD between the vonoprazan and PPI groups.The pooled results showed that there was no significant difference between the two groups in terms of the shrinkage rate at 4 weeks after ESD (MD 0.65, 95% CI -1.10-2.40;P = 0.47, I 2 = 0%) (Fig. 5A).

Discussion
Both vonoprazan and proton pump inhibitors (PPIs) are currently used to treat acid-related disorders, including artificial ulcers, after ESD [28][29][30].Some studies have shown that vonoprazan is more effective than PPIs for healing artificial ulcers after ESD [31,32].On the other hand, some studies have shown that vonoprazan and PPIs are comparable in the treatment of ESD-induced ulcers [23,26].However, whether vonoprazan is superior to PPIs remains controversial.Therefore, a meta-analysis based on RCTs was conducted to clarify the effects of vonoprazan and PPIs on the healing of artificial ulcers.According to our meta-analysis, there were no significant differences in the ulcer healing rate or shrinkage rate at 4 or 8 weeks between patients treated with vonoprazan or PPIs.Of the nine RCTs included in this meta-analysis, seven RCTs showed that vonoprazan was as efficacious as PPIs in the treatment of gastric ulcers after ESD.In contrast, the meta-analysis by Liu et al. [19] showed that vonoprazan had better efficacy in terms of ulcer shrinkage rates and healing.However, the strength of our metaanalysis is that all the included studies were RCTs, and two new well-designed studies [26,27] were added.Our findings indicated that both vonoprazan and PPIs were adequate for the healing of artificial ulcers.Notably, artificial ulcers that occur after ESD develop in hypoacidic or normal environments and are relatively mild [33].The gastric mucosal defense mechanisms are functioning, and inflammation is more localized [34].Conversely, peptic ulcers occur in vulnerable locations with hyperacidity and extend deeper and laterally [33].
Delayed postoperative bleeding is the most common complication induced by ESD.Benites-Goñi et al. reported that delayed postoperative bleeding occurred in 5-7% of patients who underwent ESD [35].Of the nine RCTs included in our meta-analysis, the rate of delayed postoperative bleeding in the vonoprazan group ranged from 0 to 5.4%.The included RCTs showed that vonoprazan had an equal or lower rate of post-ESD bleeding than did PPIs.Our meta-analysis showed that vonoprazan significantly reduced postoperative bleeding compared with PPIs.Similarly, Shiratori Y et al. [36] conducted a nationwide population-based study and reported that vonoprazan had a lower postoperative bleeding rate than did PPIs.
With respect to AEs, our meta-analysis showed that vonoprazan had a significantly lower rate of adverse events than did PPIs.In contrast, the meta-analysis conducted by Xu et al. [37] demonstrated that the incidence of adverse events was similar between vonoprazan and PPIs (P = 0.66).There are several differences between our meta-analysis and that of Xu et al. [37] Only RCTs were included in our meta-analysis, while RCTs and cohort and single-arm studies were included in the meta-analysis by Xu et al. [37] In addition, only patients with gastric ESD-induced ulcers were included in our meta-analysis, while patients with H. pylori infection, gastroesophageal reflux disease, peptic ulcer disease and ESD-induced ulcers were included in the meta-analysis by Xu et al. [37] Notably, only seven RCTs were included for the comparison of adverse events in our meta-analysis.Further study is needed to evaluate the safety of vonoprazan and PPIs.There are several limitations in our study.First, the sample sizes of some of the trials included in this metaanalysis were small.Second, the patients included in this meta-analysis received different types and dosages of PPIs, which led to significant heterogeneity.The difference in the route of administration of PPIs might also lead to heterogeneity.As Ichida et al. [22] noted, their result of ulcer shrinkage rate was different to the study by Tsuchiya et al., which might be caused by the combination of oral and intravenous PPIs therapy in the latter study.On the other hand, A recent meta-analysis by Csiki et al. [38] showed that oral administration of PPIs was not inferior to the intravenous PPIs treatment in peptic ulcer bleeding after endoscopic management.So further studies are warranted.Third, all the trials included in this study were conducted in Japan, and thus, the results may not be applicable to other races.

Fig. 4 Fig. 3
Fig. 4 Forest plots of delayed postoperative bleeding (A) and ulcer perforation (B) rates in the vonoprazan and PPI groups

Fig. 5
Fig. 5 Forest plots of the ulcer shrinkage rate at 4 weeks (A) and 8 weeks (B) in the vonoprazan and PPI groups

Table 1
Baseline characteristics of the studies included Note: VPZ Vonoprazan, M/F Male/Female, U/M/L Upper/Middle/Lower Fig. 2 Quality assessment of the nine randomized controlled trials included